US3772301A - (4-substituted)4-(methylsulfinyl)methylcarbostyrils - Google Patents
(4-substituted)4-(methylsulfinyl)methylcarbostyrils Download PDFInfo
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- US3772301A US3772301A US00201208A US3772301DA US3772301A US 3772301 A US3772301 A US 3772301A US 00201208 A US00201208 A US 00201208A US 3772301D A US3772301D A US 3772301DA US 3772301 A US3772301 A US 3772301A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
COMPOUNDS OF THE FOLLOWING FORMULA:
1-R4,2-(O=),4-R1,R2,R3-1,2-DIHYDROQUINOLINE
WHEREIN R1 IS (METHYLSULFINYL)METHYL, DIMETHOXYMETHYL, ACETY(METHYLTHIO)METHYL, FORMYL OR HYDROXYMETHYL; R2 AND R3 ARE HYDROGEN, HALOGEN, LOWER ALKYL, ARALKYL, ARYL, LOWER ALKOXY, ACYLAMINO, HYDROXY OR TAKEN TOGETHER R2 AND R3 FORM ANOTHER AROMATIC RING, AND R4 IS HYDROGEN OR METHYL, ARE DESCRIBED. THE COMPOUNDS OF THIS INVENTION ARE USEFUL FOR THE TREATMENT OF ALLERGIC CONDITIONS. THE ABOVE COMPOUNDS, WHERE R1 IS (METHYLSULFINYL) METHYL, ARE PREPARED AS FOLLOWS:
1-(R4-NH-),2-(CH3-SO-CH2-CO-),R2,R3-BENZENE AND (PH)3-
P=CH-COO-CH2-CH3 -> 1-R4,2-(O=),4-(CH3-SO-CH2-),R2,
R3-1,2-DIHYDROQUINOLINE
WHEN R1 IS OTHER THAN (METHYLSULFINYL)METHYL, THEY ARE PREPARED BY TREATING THE (METHYLSULFINYL)METHYL SUBSTITUTED CARBOSTYRILS WITH ACETIC ANHYDRIDE AS SET FORTH IN THE BODY OF THE SPECIFICATION. THESE COMPOUNDS ARE USEFUL IN PROVIDING SYMPTOMATIC RELIEF OF ALLERGIC CONDITIONS SUCH AS BRONCHIAL ASTHMA.
1-R4,2-(O=),4-R1,R2,R3-1,2-DIHYDROQUINOLINE
WHEREIN R1 IS (METHYLSULFINYL)METHYL, DIMETHOXYMETHYL, ACETY(METHYLTHIO)METHYL, FORMYL OR HYDROXYMETHYL; R2 AND R3 ARE HYDROGEN, HALOGEN, LOWER ALKYL, ARALKYL, ARYL, LOWER ALKOXY, ACYLAMINO, HYDROXY OR TAKEN TOGETHER R2 AND R3 FORM ANOTHER AROMATIC RING, AND R4 IS HYDROGEN OR METHYL, ARE DESCRIBED. THE COMPOUNDS OF THIS INVENTION ARE USEFUL FOR THE TREATMENT OF ALLERGIC CONDITIONS. THE ABOVE COMPOUNDS, WHERE R1 IS (METHYLSULFINYL) METHYL, ARE PREPARED AS FOLLOWS:
1-(R4-NH-),2-(CH3-SO-CH2-CO-),R2,R3-BENZENE AND (PH)3-
P=CH-COO-CH2-CH3 -> 1-R4,2-(O=),4-(CH3-SO-CH2-),R2,
R3-1,2-DIHYDROQUINOLINE
WHEN R1 IS OTHER THAN (METHYLSULFINYL)METHYL, THEY ARE PREPARED BY TREATING THE (METHYLSULFINYL)METHYL SUBSTITUTED CARBOSTYRILS WITH ACETIC ANHYDRIDE AS SET FORTH IN THE BODY OF THE SPECIFICATION. THESE COMPOUNDS ARE USEFUL IN PROVIDING SYMPTOMATIC RELIEF OF ALLERGIC CONDITIONS SUCH AS BRONCHIAL ASTHMA.
Description
United States Patent 3,772,301 [4-SUBSTITUTED]4-(METHYLSULFINYL) METHYLCARBOSTYRILS Maximillian von Strandtmann, Rockaway, and David T. Connor, Parsippany, N.J., assignors to Warner-Lambert Company, Morris Plains, NJ. No Drawing. Filed Nov. 22, 1971, Ser. No. 201,208
Int. Cl. C07d 33/60 US. Cl. 260-283 S 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the following formula:
i O 0 01-12 s CH3 CH son R2 I z a Ph3P=C H C OZCHQCHQ to N Ra Ra I When R is other than (methylsulfinyl)methyl, they are prepared by treating the (methylsulfinyl)methyl substituted carbostyrils with acetic anhydride as set forth in the body of the specification.
These compounds are useful in providing symptomatic relief of allergic conditions such as bronchial asthma.
The present invention is concerned with 4-substituted carbostyrils having the following structural formula:
R1 R2 I wherein R is (methylsulfinyl)methyl, dimethoxymethyl, acetyl (methylthio)methyl, formyl or hydroxymethyl; R and R are hydrogen, halogen, an alkyl group having 1 to 4 carbon atoms, aralkyl, aryl, an alkoxy group having 1 to 4 carbon atoms, acylamino, hydroxy or taken together R and R form another aromatic ring, and R is hydrogen or methyl.
The above compounds exhibit anti-allergic activity in several mammalian species. For example, using test procedures described by I. Mota, Life Sciences, 7, 465 (1963); Z. Ovary and O. Bier, Proc. Soc. Exptl. Biol. Med., 81, 584 (1952) utilizing sensitized rats as the host these compounds administered at a dose of 100 mg./kg. intraparenterally have been observed to suppress allergic manifestations.
Y Generally speaking, these compounds are indicated in providing symptomatic relief in allergic manifestations such as asthma. A dose of about mg./kg. is prescribed to provide such relief.
In order to use these compounds they are formulated with pharmaceutical excipients such as sesame oil, peanut oil or water for injection into dosage forms suitable for parenteral administration.
According to the present invention the above compounds wherein R is (methylsulfinyl)methyl are prepared from the corresponding o-aminomethylsulfinylacetophenones by the following reaction scheme:
5 T on CH cmsom R2 7 a PhaP=CHCOzCHa NH N :0 R3 1 Rs 1 The 4 [(methylsulfinyl)methyl]carbostyrils are converted to 4-formylcarbostyrils by the reaction sequence shown below:
I O O--CH: *r crno o CH3 S CH3 C H R2 I 0 R2 I C H @i crnoo O O X/\ Ra I 3 I Iz/CHaOH /O CH: R ('1 H O R CI H 2 OCHa aqueous I 0 hydrochloric acid I N =0 Ra s l The 4-formylcarbostyrils can be used as synthetic intermediates in an analogous manner to the 4-substituted coumarins described in our copending application filed Oct. 22, 1971 (our Docket No. 2100.862) (U.S. Ser. No. 191,830, filed Oct. 22, 1971). An example is the reduction of the 4-formyl group to the 4-hydroxymethyl group with sodium borohydride.
CHO CHzOH B2 \A R2 I I I L Re: I R3 The following examples are included in order further to illustrate the invention.
EXAMPLE 1 0 CH3 g CH3 H 6-chloro-4[ (methylsulfinyl)methyl] carbostyril 6-chloro 2 amino-1[(methylsulfinyl)acetyl]benzene (23.1 g., 0.1 m) and (carbethoxymethylene)triphenylphosphorane (69.6 g., 0.2 m) in dioxane (500 ml.) were refiuxed for 48 hours. The reaction mixture was cooled and the product was filtered. Recrystallization from DMF gave a white crystalline solid (15 g., 60%), M.P. 275 276.
Analysis.-Calcd. for C H CINO S (percent): C, 51.67; H, 3.94; N, 5.48; Cl, 13.86; S, 12.54. Found (percent): C, 51.60; H, 4.19; N, 5.46; C1, 13.90; S, 12.46.
6-ch1oro- 1-methyl-4-[ (methylsulfinyl methyl] carbostyril Prepared by the general method described above. Recrystallization from ethanol gave yellow crystals (31% yield), M.P. 223224.
Analysis. Calcd. for C H ClNO S (percent): C, 53.43; H, 4.48; N, 5.19; Cl, 13.14; S, 11.89. Found (percent): C, 53.63; H, 4.51; N, 5.17; Cl, 13.07; S, 11.85.
EXAMPLE 3 O (iJH CI-h MeO MeO N 6,7-dimethoxy-4-[ (methylsulfinyl methyl] carbostyril Prepared by the general method outlined above with a reflux time of 68 hours. Recrystallization from DMF gave a crystalline product in 0.6% yield, M.P. 261- 263.
Analysis.-Calcd. for C H NO S (percent): C, 55.50; H, 5.37; N, 4.98; S, 11.40. Found (percent): C, 55.50; H, 5.50; N, 5.09; S, 11.38.
EXAMPLE 4 /OAc OAc CH 011 I SMc I SMe o1 ll j or m k/Mv =0 -K/\N :0
MQAO
6 chloro-4-[hydroxy(methylthio)methyl]carbostyril acetate and 6-chloro 1 acetyl-4-[hydroxy(methylthio) methyl]carbostyril acetate 6 chloro-4-[(methylsulfinyl)methyl]carbostyril (14.6 g., .05 m) in acetic anhydride (600 ml.) was refluxed for 6 hours. The substrate gradually dissolved over the first 3 hours to give a deep purple solution. The solvent was removed under reduced pressure and the residue was recrystallized from methanol to give 6-chloro-4-[hydroxymethylthio)mehyl]carbostyril acetate (5.21 g., 32%) as white crystals, M.P. 243 244.
Analysis.-Calcd. for C H ClNO S (percent): C, 52.44; H, 4.06; N, 4.70; S, 10.77. Found (percent): C, 52.36; H, 4.16; N, 4.48; S, 10.58.
A second crop crystallized out to give 6 chloro-lacetyl-4- [hydroxy (methylthio) methyl] carbostyril acetate (7.0 g., 39%) as white crystals, M.P. l03104.
Analysis.Calcd. for C H ClNO S (percent): C, 52.94; H, 4.12; N, 4.12; S, 9.41. Found (percent): C, 52.98; H, 4.19; N, 4.16; S, 10.12.
EXAMPLE 5 O C O 0 Hz SMe 6-chloro-1-methyl-4-[hydroxymethylthio] carbostyril acetate 6-chloro 1 methyl-4-[methylsulfinyl)methyl]carbostyril (340 mg., 0.013 In) in acetic anhydride (20 ml.) was refluxed for 4 hours. The solvent was removed under reduced pressure to give a brown gum which crystallized on standing. Recrystallization from methanol gave a crystalline solid (0.340 g., 87% M.P. 150151.
Analysis.Calcd. for C H ClNO S (percent): C, 53.93; H, 4.53; N, 4.49; S, 10.28. Found (percent): C, 54.08; H, 4.58; N, 4.63; S, 10.37.
EXAMPLE 6 0M0 C H 6-chloro-4-(dimethoxymethyl)carbostyril EXAMPLE 7 6-chl0ro-4-forrnylcarbostyril A suspension of 6-chloro-4-(dimethoxymethyl)carbostyril (3 g., 0.012 m) in 20% hydrochloric acid (100 ml.) was refluxed with stirring for 3 hours. The crude product was filtered 01f. Recrystallization from DMF gave yellow crystals (2.03 g., M.P. 304305.
Analysis.--Calcd. for C H ClNO (percent): C, 57.85; H, 2.91; N, 6.75; Cl, 17.08. Found (percent): C, 58.10; H, 2.95; N, 6.64; Cl, 17.05.
EXAMPLE 8 (I3HzOH 01 q 6 -chloro-4- (hydroxymethyl carbostyril We claim: 1. A compound of the formula:
omso 0H:
wherein R and R are hydrogen, halogen or an alkoxy group having 1 t0 4 carbon atoms, and R is hydrogen or methyl.
2. A compound according to claim 1 which is 6-chlor0- 4[ (methylsulfinyl) methyl] carbostyril.
3. A compound according to claim 1 which is 6-chloro- 1-methy1-4-[ (methylsulfinyl methyl] carbostyril.
4. A compound according to claim 1 which is 6,7-dimethoxy-4 (methylsulfinyl) methyl] carbostyril.
References Cited UNITED STATES PATENTS 3,438,992 4/1969 Shen 260283 S OTHER REFERENCES Takahashi et al.: Chem. Abstr. vol. 72, col. 901-82z (1970).
Chudgar et al.: Chem. Abstr. vol. 75, col. 20150a (1971).
Takahashi et al.: Chem. Abstr., vol. 67, col. 64157x (1967).
DONALD G. DAUS, Primary Examiner US. Cl. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US20120871A | 1971-11-22 | 1971-11-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3772301A true US3772301A (en) | 1973-11-13 |
Family
ID=22744912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00201208A Expired - Lifetime US3772301A (en) | 1971-11-22 | 1971-11-22 | (4-substituted)4-(methylsulfinyl)methylcarbostyrils |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4066651A (en) * | 1975-03-20 | 1978-01-03 | Imperial Chemical Industries Limited | Alkanoic acid 2-quinoline derivatives |
| US4124587A (en) * | 1976-03-01 | 1978-11-07 | Sandoz, Inc. | 4-Hydroxy-3-sulfinyl-quinolin-2(1H)-ones |
| US4128649A (en) * | 1977-06-29 | 1978-12-05 | Sandoz, Inc. | 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters |
| US4138490A (en) * | 1975-03-20 | 1979-02-06 | Imperial Chemical Industries Limited | Analgesic compositions containing 1,2-dihydro-2-oxoquinol-4-ylpropionic acid derivatives |
| US4187310A (en) * | 1975-03-20 | 1980-02-05 | Imperial Chemical Industries Limited | 1,2-Dihydro-2-oxoquinol-4-ylacetic acid derivatives and pharmaceutical compositions |
| US4190659A (en) * | 1973-08-27 | 1980-02-26 | Sandoz, Inc. | Pharmaceutical preparation and use of 4-hydroxy-2-quinolinone-3-carboxylic acid esters |
| US4273930A (en) * | 1977-06-20 | 1981-06-16 | Sandoz, Inc. | 4-Hydroxy-2-quinolinone-3-carboxylic acid esters |
| US4281131A (en) * | 1977-06-20 | 1981-07-28 | Sandoz, Inc. | 4-Hydroxy-2-quinolinone-3-carboxylic acids and salts thereof |
| US4302460A (en) * | 1979-03-27 | 1981-11-24 | The Boots Company Limited | 4-Quinolinones having antihypertensive activity |
| US4442109A (en) * | 1980-09-26 | 1984-04-10 | The Boots Company Limited | 3-Methylthiomethyl-and 3-methylsulfinylmethyl-4-quinolinones useful for treating hypertension |
-
1971
- 1971-11-22 US US00201208A patent/US3772301A/en not_active Expired - Lifetime
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4190659A (en) * | 1973-08-27 | 1980-02-26 | Sandoz, Inc. | Pharmaceutical preparation and use of 4-hydroxy-2-quinolinone-3-carboxylic acid esters |
| US4066651A (en) * | 1975-03-20 | 1978-01-03 | Imperial Chemical Industries Limited | Alkanoic acid 2-quinoline derivatives |
| US4138490A (en) * | 1975-03-20 | 1979-02-06 | Imperial Chemical Industries Limited | Analgesic compositions containing 1,2-dihydro-2-oxoquinol-4-ylpropionic acid derivatives |
| US4187310A (en) * | 1975-03-20 | 1980-02-05 | Imperial Chemical Industries Limited | 1,2-Dihydro-2-oxoquinol-4-ylacetic acid derivatives and pharmaceutical compositions |
| US4124587A (en) * | 1976-03-01 | 1978-11-07 | Sandoz, Inc. | 4-Hydroxy-3-sulfinyl-quinolin-2(1H)-ones |
| US4273930A (en) * | 1977-06-20 | 1981-06-16 | Sandoz, Inc. | 4-Hydroxy-2-quinolinone-3-carboxylic acid esters |
| US4281131A (en) * | 1977-06-20 | 1981-07-28 | Sandoz, Inc. | 4-Hydroxy-2-quinolinone-3-carboxylic acids and salts thereof |
| US4128649A (en) * | 1977-06-29 | 1978-12-05 | Sandoz, Inc. | 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters |
| US4302460A (en) * | 1979-03-27 | 1981-11-24 | The Boots Company Limited | 4-Quinolinones having antihypertensive activity |
| US4442109A (en) * | 1980-09-26 | 1984-04-10 | The Boots Company Limited | 3-Methylthiomethyl-and 3-methylsulfinylmethyl-4-quinolinones useful for treating hypertension |
| US4447435A (en) * | 1980-09-26 | 1984-05-08 | The Boots Company Plc | 3-Methylsulfonylmethyl-4-quinolinones useful for treating hypertension |
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